脂肪间充质干细胞来源的外泌体通过促进 miR-205 介导的心脏血管生成来减轻心肌梗死损伤。

BACKGROUND: Acute myocardial infarction is a major health problem and is the leading cause of death worldwide. Myocardial apoptosis induced by myocardial infarction injury is involved in the pathophysiology of heart failure. Therapeutic stem cell therapy has the potential to be an effective and favorable treatment for ischemic heart disease. Exosomes derived from stem cells have been shown to effectively repair MI injury-induced cardiomyocyte damage. However, the cardioprotective benefits of adipose tissue-derived mesenchymal stem cell (ADSC)-Exos remain unknown. This study aimed to investigate the protective effects of exosomes from ADSC on the hearts of MI-treated mice and to explore the underlying mechanisms. METHODS: Cellular and molecular mechanisms were investigated using cultured ADSCs. On C57BL/6J mice, we performed myocardial MI or sham operations and assessed cardiac function, fibrosis, and angiogenesis 4 weeks later. Mice were intramyocardially injected with ADSC-Exos or vehicle-treated ADSCs after 25 min following the MI operation. RESULTS: Echocardiographic experiments showed that ADSC-Exos could significantly improve left ventricular ejection fraction, whereas ADSC-Exos administration could significantly alleviate MI-induced cardiac fibrosis. Additionally, ADSC-Exos treatment has been shown to reduce cardiomyocyte apoptosis while increasing angiogenesis. Molecular experiments found that exosomes extracted from ADSCs can promote the proliferation and migration of microvascular endothelial cells, facilitate angiogenesis, and inhibit cardiomyocytes apoptosis through miRNA-205. We then transferred isolated exosomes from ADSCs into MI-induced mice and observed decreased cardiac fibrosis, increased angiogenesis, and improved cardiac function. We also observed increased apoptosis and decreased expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in HMEC-1 transfected with a miRNA-205 inhibitor. CONCLUSION: In summary, these findings show that ADSC-Exos can alleviate cardiac injury and promote cardiac function recovery in MI-treated mice via the miRNA-205 signaling pathway. ADSC-Exos containing miRNA205 have a promising therapeutic potential in MI-induced cardiac injury.

背景：急性心肌梗死是一个重大的健康问题，也是全球范围内导致死亡的主要原因。心肌梗死损伤诱导的心肌细胞凋亡参与心力衰竭的病理生理过程。治疗性干细胞疗法有可能成为缺血性心脏病的一种有效且有利的治疗方法。已证明干细胞来源的外泌体可有效修复 MI 损伤诱导的心肌细胞损伤。然而，脂肪组织来源的间充质干细胞（ADSC）-Exos 的心脏保护益处尚不清楚。本研究旨在探讨 ADSC 衍生的外泌体对 MI 治疗小鼠心脏的保护作用，并探讨其潜在机制。

方法：使用培养的 ADSC 研究细胞和分子机制。在 C57BL/6J 小鼠上进行心肌 MI 或假手术，并在 4 周后评估心脏功能、纤维化和血管生成。在 MI 手术后 25 分钟，通过心肌内注射 ADSC-Exos 或对照处理的 ADSC。

结果：超声心动图实验表明，ADSC-Exos 可显著改善左心室射血分数，而 ADSC-Exos 给药可显著减轻 MI 诱导的心脏纤维化。此外，ADSC-Exos 治疗可减少心肌细胞凋亡，同时增加血管生成。分子实验发现，从 ADSC 中提取的外泌体可以促进微血管内皮细胞的增殖和迁移，促进血管生成，并通过 miRNA-205 抑制心肌细胞凋亡。然后，我们将从 ADSC 中分离的外泌体转染到 MI 诱导的小鼠中，观察到心脏纤维化减少、血管生成增加和心脏功能改善。我们还观察到转染 miRNA-205 抑制剂的 HMEC-1 中凋亡增加和缺氧诱导因子-1α 和血管内皮生长因子表达减少。

结论：总之，这些发现表明，ADSC-Exos 可以通过 miRNA-205 信号通路减轻 MI 治疗小鼠的心脏损伤并促进心脏功能恢复。含 miRNA205 的 ADSC-Exos 在 MI 诱导的心脏损伤中具有有前途的治疗潜力。